US2009069323A1PendingUtilityA1
11beta-hsdi inhibitors
Est. expiryNov 8, 2024(expired)· nominal 20-yr term from priority
A61P 9/08A61P 3/06A61P 3/04A61P 9/10A61P 25/08A61P 3/10A61P 27/02A61P 25/00A61P 35/00A61P 25/28A61P 25/24A61P 19/10A61P 13/12C07D 237/24A61P 1/18C07D 213/79C07C 311/19
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Claims
Abstract
The invention relates to compounds of formula (I) wherein A, Y, Z 1 , Z 2 , R 1 to R 3 and X 1 to X 4 have the meaning as cited in the description and the claims. For example A is 4′-fluorobiphen-4-yl; Y is —S(O) 2 NH—; R 1 , R 2 are H; X 1 , X 2 , X 4 are CH; X 3 is C—F; Z 1 is ═O; and Z 2 -R 3 is N(CH 2 CH 3 ) 2 . Said compounds are useful as 11β-HSD1 inhibitors. The invention also relates to the preparation of such compounds as well as the production and use as medicament.
Claims
exact text as granted — not AI-modified1 - 28 . (canceled)
29 . A compound of formula (I)
or a pharmaceutically acceptable salt, prodrug or metabolite thereof, wherein
X 1 , X 2 , X 3 , X 4 are independently selected from the group consisting of N; and CR 4 , wherein R 4 is independently H; halogen; CN; C(O)OR 4a ; C(O)N(R 4a R 4b ); OR 4a ; N(R 4a R 4b ); phenyl; C 1-6 alkyl; or C 3-7 cycloalkyl, wherein C 1-6 alkyl and C 3-7 cycloalkyl are optionally substituted with one or more halogen, which are the same or different;
R 4a , R 4b are independently selected from the group consisting of H; C 1-6 alkyl; and C 3-7 cycloalkyl;
R 1 , R 2 are independently selected from the group consisting of H; C 1-6 alkyl; C 3-7 cycloalkyl; and halogen, wherein C 1-6 alkyl and C 3-7 cycloalkyl are optionally substituted with halogen;
Optionally R 1 , R 2 are combined to form oxo (═O);
Y is —N(R 1a )S(O) 2 —; —S(O) 2 N(R 1b )—; or —N(R 1a )S(O) 2 N(R 1b )—;
A is T; or C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted with one or more R 5 , wherein R 5 is independently halogen; CN; COOR 6 ; OR 6 ; C(O)N(R 6 R 6a ); S(O) 2 N(R 6 R 6a ); S(O)N(R 6 R 6a ); S(O) 2 R 6 ; N(R 6 )S(O) 2 N(R 6a R 6b ); SR 6 ; N(R 6 R 6a ); OC(O)R 6 ; N(R 6 )C(O)R 6a ; N(R 6 )S(O) 2 R 6a ; N(R 6 )S(O)R 6a ; N(R 6 )C(O)N(R 6a R 6b ); N(R 6 )C(CO)OR 6a ; OC(O)N(R 6 R 6a ); or T;
R 1a , R 1b are independently selected from the group consisting of H; allyl; benzyl; CH 2 —C(O)NH 2 ; CH 2 —COOH; CH 2 —C(O)O—C 1-6 alkyl; C 1-6 alkyl; and C 3-7 cycloalkyl, wherein C 1-6 alkyl and C 3-7 cycloalkyl are optionally substituted with one or more R 1c , wherein R 1c is independently halogen; C 1-6 alkyl; —CH═CH 2 ; phenyl; C(O)NH 2 ; COOH; C(O)O—C 1-6 alkyl or C 3-7 cycloalkyl;
Optionally A and R 1a form together with the nitrogen to which they are attached to a heterocycle or heterobicycle optionally substituted with one or more R 7 , which are the same or different;
R 6 , R 6a R 6b are independently selected from the group consisting of H; C 1-6 alkyl; and T, wherein C 1-6 alkyl is optionally substituted with one or more halogen, which are the same of different;
T is C 3-7 cycloalkyl; heterocyclyl; heterobicyclyl; phenyl; naphthyl; indenyl; indanyl; tetralinyl; decalinyl; or adamantyl, wherein T is optionally substituted with one or more R 7 , which are the same or different;
R 7 is independently halogen; CN; COOR 8 ; OR 8 ; C(O)N(R 8 R 8a ); S(O) 2 N(R 8 R 8a ); S(O)N(R 8 R 8a ); S(O) 2 R 8 ; N(R 8 )S(O) 2 N(R 8a R 8b ); SR 8 ; N(R 8 R 8a ); OC(O)R 8 ; N(R 8 )C(O)R 8a ; N(R 8 )S(O) 2 R 8a ; N(R 8 )S(O)R 8a ; N(R 8 )C(O)N(R 8a R 8b ); N(R 8 )C(O)OR 8a ; OC(O)N(R 8 R 8a ); oxo (═O), where the ring is at least partially saturated; C(O)R 8 ; T 1 ; or C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted with one or more R 9 ;
R 8 , R 8a , R 8b are independently selected from the group consisting of H; T 1 ; and C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted with one or more R 10 ;
R 9 , R 10 are independently selected from the group consisting of halogen; CN; COOR 11 ; OR 11 ; C(O)R 11 ; C(O)N(R 11 R 11a ); S(O) 2 N(R 11 R 11a ); S(O)N(R 11 R 11a ); S(O) 2 R 11 ; N(R 11 )S(O) 2 N(R 11a R 11b ); SR 11 ; N(R 11 R 11a ); OC(O)R 11 ; N(R 11 )C(O)R 11a ; N(R 11 )SO 2 R 11a ; N(R 11 )S(O)R 11a ; N(R 11 )C(O)N(R 11a R 11b ); N(R 11 )C(O)OR 11a ; OC(O)N(R 11 R 11a ); and T 1 ;
R 11 , R 11a , R 11b are independently selected from the group consisting of H; C 1-6 alkyl; and T 1 ;
T 1 is C 3-7 cycloalkyl; heterocyclyl; heterobicyclyl; phenyl; naphthyl; indenyl; indanyl; tetralinyl; decalinyl; or adamantyl, wherein T 1 is optionally substituted with one or more R 12 , wherein R 12 is independently halogen; CN; COOR 13 ; OR 13 ; C(O)N(R 13 R 13a ); S(O) 2 N(R 13 R 13a ); S(O)N(R 13 R 13a ); S(O) 2 R 13 ; N(R 13 )S(O) 2 N(R 13a R 13b ); SR 13 ; N(R 13 R 13a ); OC(O)R 13 ; N(R 13 )C(O)R 13a ; N(R 13 )S(O) 2 R 13a ; N(R 13 )S(O)R 13a ; N(R 13 )C(O)N(R 13a R 13b ); N(R 13 )C(O)OR 13a ; OC(O)N(R 13 R 13a ); oxo (═O), where the ring is at least partially saturated; C(O)R 13 ; C 1-6 alkyl; phenyl; C 3-7 cycloalkyl; or heterocyclyl, wherein C 1-6 alkyl; phenyl; C 3-7 cycloalkyl; and heterocyclyl are optionally substituted with one or more halogen, which are the same or different;
R 13 , R 13a , R 13b are independently selected from the group consisting of H; C 1-6 alkyl; phenyl; C 3-7 cycloalkyl; and heterocyclyl, wherein C 1-6 alkyl; phenyl; C 3-7 cycloalkyl; and heterocyclyl are optionally substituted with one or more halogen, which are the same or different;
Z 1 is ═O or ═S;
Optionally Z 1 is ═N—R 15 and R 15 , R 3 jointly form together with the atoms to which they are attached a heterocycle or heterobicycle, wherein the heterocycle or heterobicycle is optionally substituted with one or more R 16 , provided that the heterocycle is other than
Z 2 is O; S; or N—R 14 ;
R 3 , R 14 are independently selected from the group consisting of H; T 2 ; C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted with one or more R 17 , provided that when one of R 3 and R 14 is H and the other is ethyl, R 17 is other than —COOH;
Optionally R 3 , R 14 jointly form together with the nitrogen to which they are attached a heterocycle or heterobicycle, wherein the heterocycle or heterobicycle is optionally substituted with one or more R 18 , provided that the heterobicycle is other than unsubstituted or in 3, 6 and/or 7 position substituted 1,2,3,4-tetrahydroquinoline and its 4-oxa, -thia, -aza and/or 8-aza derivatives;
T 2 is C 3-7 cycloalkyl, heterocyclyl; heterobicyclyl; phenyl; naphthyl; indenyl; indanyl; tetralinyl; decalinyl; or adamantyl, wherein T 2 is optionally substituted with one or more R 19 ; provided that when A is phenyl; Y is —S(O) 2 NH—, wherein the sulfur is attached to A;
R 1 , R 2 are H; X 1 , X 3 , X 4 are CH; X 2 is C—R 4 , wherein R 4 is OCH 3 ; Z 1 is ═O; and Z 2 is NH, T 2 is other than unsubstituted phenyl;
R 16 , R 18 , R 19 are independently selected from the group consisting of halogen; CN; COOR 20 ; OR 20 ; C(O)N(R 20 R 20a ); S(O) 2 N(R 20 R 20a ); S(O)N(R 20 R 20a ); S(O) 2 R 20 ; N(R 20 )S(O) 2 N(R 20a R 20b ); SR 20 ; N(R 20 R 20a ); OC(O)R 20 ; N(R 20 )C(O)R 20a ; N(R 20 )S(O) 2 R 20a ; N(R 20 )S(O)R 20a ; N(R 20 )C(O)N(R 20a R 20b ); N(R 20 )C(O)OR 20a ; OC(O)N(R 20 R 20a ); oxo (═O), where the ring is at least partially saturated; C(O)R 20 ; C 1-6 alkyl; phenyl; heterocyclyl; and C 3-7 cycloalkyl, wherein C 1-6 alkyl; phenyl; heterocyclyl; and C 3-7 cycloalkyl are optionally substituted with one or more R 21 ;
R 20 , R 20a , R 20b are independently selected from the group consisting of H; phenyl; heterocyclyl; C 3-7 cycloalkyl and C 1-6 alkyl, wherein phenyl; heterocyclyl; C 3-7 cycloalkyl; and C 1-6 alkyl are optionally substituted with one or more halogen, which are the same or different;
R 17 , R 21 are independently selected from the group consisting of halogen; CN; COOR 22 ; OR 22 ; C(O)R 22 ; C(O)N(R 22 R 22a ); S(O) 2 N(R 22 R 22a ); S(O)N(R 22 R 22a ); S(O) 2 R 22 ; N(R 22 )S(O) 2 N(R 22a R 22b ); SR 22 ; N(R 22 R 22a ); OC(O)R 22 ; N(R 22 )C(O)R 22a ; N(R 22 )SO 2 R 22a ; N(R 22 )S(O)R 22a ; N(R 22 )C(O)N(R 22a R 22b ); N(R 22 )C(O)OR 22a ; OC(O)N(R 22 R 22a ); C 1-6 alkyl; phenyl; heterocyclyl; and C 3-7 cycloalkyl, wherein C 1-6 alkyl; phenyl; heterocyclyl; and C 3-7 cycloalkyl are optionally substituted with one or more R 23 ;
R 22 , R 22a , R 22b are independently selected from the group consisting of H; phenyl; heterocyclyl; C 3-7 cycloalkyl and C 1-6 alkyl, wherein phenyl; heterocyclyl; C 3-7 cycloalkyl; and C 1-6 alkyl are optionally substituted with one or more R 23a ;
R 23 , R 23a are independently selected from the group consisting of halogen; CN; COOR 24 ; OR 24 ; C(O)R 24 ; C(O)N(R 24 R 24a ); S(O) 2 N(R 24 R 24a ); S(O)N(R 24 R 24a ); S(O) 2 R 24 ; N(R 24 )S(O) 2 N(R 24a R 24b ); SR 24 ; N(R 24 R 24a ); OC(O)R 24 ; N(R 24 )C(O)R 24a ; N(R 24 )SO 2 R 24a ; N(R 24 )S(O)R 24a ; N(R 24 )C(O)N(R 24a R 24b ); N(R 24 )C(O)OR 24a ; OC(O)N(R 24 R 24a ); and C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted with one or more halogen, which are the same or different;
R 24 , R 24a , R 24b are independently selected from the group consisting of H; C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted with one or more halogen, which are the same or different,
provided that the compound of formula (I) is other than N-[1-(3-aminocarbonyl-4-hydroxyphenyl)-2,2,2-trichloroethyl]-4-chlorobenzenesulfonamide.
30 . A compound according to claim 29 , wherein at most one of X 1 , X 2 , X 3 and X 4 are N.
31 . A compound according to claim 29 , wherein R 1 and R 2 are H or combined to form ═O.
32 . A compound according to claim 29 , wherein R 4 is F; Cl; Br; CH 3 ; OCH 3 , NH 2 ; or phenyl.
33 . A compound according to claim 29 , wherein Y is —*S(O) 2 —NH— or —*S(O) 2 —N(CH 3 )— wherein the atom marked with an asterisk is attached to A.
34 . A compound according to claim 29 , wherein A is phenyl, adamantyl; C 3-7 cycloalkyl; heterocyclyl; or C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted with T.
35 . A compound according to claim 34 , wherein A is phenyl; cyclohexyl; thiophenyl; benzothiophenyl; naphthyl; diazolyl; or pyridyl.
36 . A compound according to of claim 29 , wherein A is T and T is optionally substituted with up to 3 R 7 , independently being F; Cl; CH 3 ; OCH 3 ; N(CH 3 ) 2 ; T 1 ; OT 1 ; or NHT 1 .
37 . A compound according to claim 36 , wherein T 1 is phenyl, which is optionally substituted with up to three halogens, independently being F; and Cl.
38 . A compound according to claim 29 , wherein A is T and T is heterobicyclyl.
39 . A compound according to claim 38 , wherein heterobicyclyl is decahydroquinoline or tetrahydroisoquinoline and wherein the ring nitrogen is directly linked to the sulphur of the sulphonamide group representing Y.
40 . A compound according to claim 29 , wherein Z 1 is ═O and Z 2 is —NR 14 .
41 . A compound according to claim 29 , wherein R 14 is H.
42 . A compound according to claim 29 , wherein R 3 is phenyl; benzyl; heterocyclyl; C 3-7 cycloalkyl; or C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted with O—C 1-6 alkyl or C 3-7 cycloalkyl.
43 . A compound according to claim 29 , wherein R 3 is T 2 and T 2 is substituted with up to three R 19 , independently being F; Cl; CH 3 ; OCH 3 ; N(CH 3 ) 2 ; C(O)OH; C(O)OCH 3 ; CF 3 ; or C(O)NH 2 .
44 . A compound according to claim 43 , wherein T 2 is phenyl; cyclohexyl; or pyridyl.
45 . A compound according to claim 29 , wherein R 3 , R 14 are independently H or C 1-6 alkyl, independently being ethyl; isopropyl; n-propyl; n-butyl, wherein C 1-6 alkyl is optionally substituted with N(CH 3 ) 2 ; or N(C 2 H 5 ) 2 .
46 . A compound according to claim 29 , wherein Z 1 is ═N—R 15 and R 15 , R 3 jointly form a heterocycle.
47 . A compound according to claim 46 , wherein the heterocycle is oxazole; oxadiazole; diazole; or triazole, wherein the heterocycle is optionally substituted with one R 16 being C 1-6 alkyl, optionally substituted with N(CH 3 ) 2 or N(CH 2 CH 3 ) 2 ; C 3-7 cycloalkyl; phenyl; or heterocyclyl.
48 . A compound according to claim 46 , wherein R 16 is methyl; ethyl; iso-propyl; cyclohexyl; phenyl; or piperidinyl.
49 . A compound according to claim 29 , wherein R 3 , R 14 jointly form a heterocycle.
50 . A compound according to claim 49 , wherein the heterocycle is piperazine; morpholine; piperidine; or pyrrolidine, and wherein the heterocycle is optionally substituted with methyl.
51 . A pharmaceutical composition comprising a compound of formula (I)
or a pharmaceutically acceptable salt, prodrug or metabolite thereof, wherein X 1 , X 2 , X 3 , X 4 are independently selected from the group consisting of N; and CR 4 , wherein R 4 is independently H; halogen; CN; C(O)OR 4a ; C(O)N(R 4a R 4b ); OR 4a ; N(R 4a R 4b ); phenyl; C 1-6 alkyl; or C 3-7 cycloalkyl, wherein C 1-6 alkyl and C 3-7 cycloalkyl are optionally substituted with one or more halogen, which are the same or different;
R 4a , R 4b are independently selected from the group consisting of H; C 1-6 alkyl; and C 3-7 cycloalkyl;
R 1 , R 2 are independently selected from the group consisting of H; C 1-6 alkyl; C 3-7 cycloalkyl; and halogen, wherein C 1-6 alkyl and C 3-7 cycloalkyl are optionally substituted with halogen;
Optionally R 1 , R 2 are combined to form oxo (═O);
Y is —N(R 1a )S(O) 2 —; —S(O) 2 N(R 1b )—; or —N(R 1a )S(O) 2 N(R 1b )—;
A is T; or C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted with one or more R 5 , wherein R 5 is independently halogen; CN; COOR 6 ; OR 6 ; C(O)N(R 6 R 6a ); S(O) 2 N(R 6 R 6a ); S(O)N(R 6 R 6a ); S(O) 2 R 6 ; N(R 6 )S(O) 2 N(R 6a R 6b ); SR 6 ; N(R 6 R 6a ); OC(O)R 6 ; N(R 6 )C(O)R 6a ; N(R 6 )S(O) 2 R 6a ; N(R 6 )S(O)R 6a ; N(R 6 )C(O)N(R 6a R 6b ); N(R 6 )C(CO)OR 6a ; OC(O)N(R 6 R 6a ); or T;
R 1a , R 1b are independently selected from the group consisting of H; allyl; benzyl; CH 2 —C(O)NH 2 ; CH 2 —COOH; CH 2 —C(O)O—C 1-6 alkyl; C 1-6 alkyl; and C 3-7 cycloalkyl, wherein C 1-6 alkyl and C 3-7 cycloalkyl are optionally substituted with one or more R 1c , wherein R 1c is independently halogen; C 1-6 alkyl; —CH═CH 2 ; phenyl; C(O)NH 2 ; COOH; C(O)O—C 1-6 alkyl or C 3-7 cycloalkyl;
Optionally A and R 1a form together with the nitrogen to which they are attached to a heterocycle or heterobicycle optionally substituted with one or more R 7 , which are the same or different;
R 6 , R 6a R 6b are independently selected from the group consisting of H; C 1-6 alkyl; and T, wherein C 1-6 alkyl is optionally substituted with one or more halogen, which are the same of different;
T is C 3-7 cycloalkyl; heterocyclyl; heterobicyclyl; phenyl; naphthyl; indenyl; indanyl; tetralinyl; decalinyl; or adamantyl, wherein T is optionally substituted with one or more R 7 , which are the same or different;
R 7 is independently halogen; CN; COOR 8 ; OR 8 ; C(O)N(R 8 R 8a ); S(O) 2 N(R 8 R 8a ); S(O)N(R 8 R 8a ); S(O) 2 R 8 ; N(R 8 )S(O) 2 N(R 8a R 8b ); SR 8 ; N(R 8 R 8a ); OC(O)R 8 ; N(R 8 )C(O)R 8a ; N(R 8 )S(O) 2 R 8a ; N(R 8 )S(O)R 8a ; N(R 8 )C(O)N(R 8a R 8b ); N(R 8 )C(O)OR 8a ; OC(O)N(R 8 R 8a ); oxo (═O), where the ring is at least partially saturated; C(O)R 8 ; T 1 ; or C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted with one or more R 9 ;
R 8 , R 8a , R 8b are independently selected from the group consisting of H; T 1 ; and C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted with one or more R 10 ;
R 9 , R 10 are independently selected from the group consisting of halogen; CN; COOR 11 ; OR 11 ; C(O)R 11 ; C(O)N(R 11 R 11a ); S(O) 2 N(R 11 R 11a ); S(O)N(R 11 R 11a ); S(O) 2 R 11 ; N(R 11 )S(O) 2 N(R 11a R 11b ); SR 11 ; N(R 11 R 11a ); OC(O)R 11 ; N(R 11 )C(O)R 11a ; N(R 11 )SO 2 R 11a ; N(R 11 )S(O)R 11a ; N(R 11 )C(O)N(R 11a R 11b ); N(R 11 )C(O)OR 11a ; OC(O)N(R 11 R 11a ); and T 1 ;
R 11 , R 11a , R 11b are independently selected from the group consisting of H; C 1-16 alkyl; and T 1 ;
T 1 is C 3-7 cycloalkyl; heterocyclyl; heterobicyclyl; phenyl; naphthyl; indenyl; indanyl; tetralinyl; decalinyl; or adamantyl, wherein T 1 is optionally substituted with one or more R 12 , wherein R 12 is independently halogen; CN; COOR 13 ; OR 13 ; C(O)N(R 13 R 13a ); S(O) 2 N(R 13 R 13a ); S(O)N(R 13 R 13a ); S(O) 2 R 13 ; N(R 13 )S(O) 2 N(R 13a R 13b ); SR 13 ; N(R 13 R 13a ); OC(O)R 13 ; N(R 13 )C(O)R 13a ; N(R 13 )S(O) 2 R 13a ; N(R 13 )S(O)R 13a ; N(R 13 )C(O)N(R 13a R 13b ); N(R 13 )C(O)OR 13a ; OC(O)N(R 13 R 13a ); oxo (═O), where the ring is at least partially saturated; C(O)R 13 ; C 1-6 alkyl; phenyl; C 3-7 cycloalkyl; or heterocyclyl, wherein C 1-6 alkyl; phenyl; C 3-7 cycloalkyl; and heterocyclyl are optionally substituted with one or more halogen, which are the same or different;
R 13 , R 13a , R 13b are independently selected from the group consisting of H; C 1-6 alkyl; phenyl; C 3-7 cycloalkyl; and heterocyclyl, wherein C 1-6 alkyl; phenyl; C 3-7 cycloalkyl; and heterocyclyl are optionally substituted with one or more halogen, which are the same or different;
Z 1 is ═O or ═S;
Optionally Z 1 is ═N—R 15 and R 15 , R 3 jointly form together with the atoms to which they are attached a heterocycle or heterobicycle, wherein the heterocycle or heterobicycle is optionally substituted with one or more R 16 ;
Z is O; S; or N—R 14 ;
R 3 , R 14 are independently selected from the group consisting of H; T 2 ; C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted with one or more R 17 , provided that when one of R 3 and R 14 is H and the other is ethyl, R 17 is other than —COOH; alkyl; phenyl; heterocyclyl; and C 3-7 cycloalkyl, wherein C 1-6 alkyl; phenyl; heterocyclyl; and C 3-7 cycloalkyl are optionally substituted with one or more R 23 ;
R 22 , R 22a , R 22b are independently selected from the group consisting of H; phenyl; heterocyclyl; C 3-7 cycloalkyl and C 1-6 alkyl, wherein phenyl; heterocyclyl; C 3-7 cycloalkyl; and C 1-6 alkyl are optionally substituted with one or more R 23a ;
R 23 , R 23a are independently selected from the group consisting of halogen; CN; COOR 24 ; OR 24 ; C(O)R 24 ; C(O)N(R 24 R 24a ); S(O) 2 N(R 24 R 24a ); S(O)N(R 24 R 24a ); S(O) 2 R 24 ; N(R 24 )S(O) 2 N(R 24a R 24b ); SR 24 ; N(R 24 R 24a ); OC(O)R 24 ; N(R 24 )C(O)R 24a ; N(R 24 )SO 2 R 24a ; N(R 24 )S(O)R 24a ; N(R 24 )C(O)N(R 24a R 24b ); N(R 24 )C(O)OR 24a ; OC(O)N(R 24 R 24a ); and C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted with one or more halogen, which are the same or different;
R 24 , R 24a , R 24b are independently selected from the group consisting of H; C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted with one or more halogen, which are the same or different, together with a pharmaceutically acceptable carrier, optionally in combination with one or more other pharmaceutical compositions.
52 . A pharmaceutical composition comprising a compound of formula (I)
Optionally R 3 , R 14 jointly form together with the nitrogen to which they are attached a heterocycle or heterobicycle, wherein the heterocycle or heterobicycle is optionally substituted with one or more R 18 , provided that the heterobicycle is other than unsubstituted or in 3, 6 and/or 7 position substituted 1,2,3,4-tetrahydroquinoline and its 4-oxa, -thia, -aza and/or 8-aza derivatives; T 2 is C 3-7 cycloalkyl, heterocyclyl; heterobicyclyl; phenyl; naphthyl; indenyl; indanyl; tetralinyl; decalinyl; or adamantyl, wherein T 2 is optionally substituted with one or more R 19 ; provided that when A is phenyl; Y is —S(O) 2 NH—, wherein the sulfur is attached to A; R 1 , R 2 are H; X 1 , X 3 , X 4 are CH; X 2 is C—R 4 , wherein R 4 is OCH 3 ; Z 1 is ═O; and Z 2 is NH, T 2 is other than unsubstituted phenyl; R 16 , R 18 , R 19 are independently selected from the group consisting of halogen; CN; COOR 20 ; OR 20 ; C(O)N(R 20 R 20a ); S(O) 2 N(R 20 R 20a ); S(O)N(R 20 R 20a ); S(O) 2 R 20 ; N(R 20 )S(O) 2 N(R 20a R 20b ); SR 20 ; N(R 20 R 20a ); OC(O)R 20 ; N(R 20 )C(O)R 20a ; N(R 20 )S(O) 2 R 20a ; N(R 20 )S(O)R 20a ; N(R 20 )C(O)N(R 20a R 20b ); N(R 20 )C(O)OR 20a ; OC(O)N(R 20 R 20a ); oxo (═O), where the ring is at least partially saturated; C(O)R 20 ; C 1-6 alkyl; phenyl; heterocyclyl; and C 3-7 cycloalkyl, wherein C 1-6 alkyl; phenyl; heterocyclyl; and C 3-7 cycloalkyl are optionally substituted with one or more R 21 ; R 20 , R 20a , R 20b are independently selected from the group consisting of H; phenyl; heterocyclyl; C 3-7 cycloalkyl and C 1-6 alkyl, wherein phenyl; heterocyclyl; C 3-7 cycloalkyl; and C 1-6 alkyl are optionally substituted with one or more halogen, which are the same or different; R 17 , R 21 are independently selected from the group consisting of halogen; CN; COOR 22 ; OR 22 ; C(O)R 22 ; C(O)N(R 22 R 22a ); S(O) 2 N(R 22 R 22a ); S(O)N(R 22 R 22a ); S(O) 2 R 22 ; N(R 22 )S(O) 2 N(R 22a R 22b ); SR 22 ; N(R 22 R 22a ); OC(O)R 22 ; N(R 22 )C(O)R 22a ; N(R 22 )SO 2 R 22a ; N(R 22 )S(O)R 22a ; N(R 22 )C(O)N(R 22a R 22b ); N(R 22 )C(O)OR 22a ; OC(O)N(R 22 R 22a ); C 1-6
or a pharmaceutically acceptable salt, prodrug or metabolite thereof, wherein
X 1 , X 2 , X 3 , X 4 are independently selected from the group consisting of N; and CR 4 , wherein R 4 is independently H; halogen; CN; C(O)OR 4a ; C(O)N(R 4a R 4b ); OR 4a ; N(R 4a R 4b ); phenyl; C 1-6 alkyl; or C 3-7 cycloalkyl, wherein C 1-6 alkyl and C 3-7 cycloalkyl are optionally substituted with one or more halogen, which are the same or different;
R 4a , R 4b are independently selected from the group consisting of H; C 1-6 alkyl; and C 3-7 cycloalkyl;
R 1 , R 2 are independently selected from the group consisting of H; C 1-6 alkyl; C 3-7 cycloalkyl; and halogen, wherein C 1-6 alkyl and C 3-7 cycloalkyl are optionally substituted with halogen;
Optionally R 1 , R 2 are combined to form oxo (═O);
Y is —N(R 1a )S(O) 2 —; —S(O) 2 N(R 1b )—; or —N(R 1a )S(O) 2 N(R 1b )—;
A is T; or C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted with one or more R 5 , wherein R 5 is independently halogen; CN; COOR 6 ; OR 6 ; C(O)N(R 6 R 6a ); S(O) 2 N(R 6 R 6a ); S(O)N(R 6 R 6a ); S(O) 2 R 6 ; N(R 6 )S(O) 2 N(R 6a R 6b ); SR 6 ; N(R 6 R 6a ); OC(O)R 6 ; N(R 6 )C(O)R 6a ; N(R 6 )S(O) 2 R 6a ; N(R 6 )S(O)R 6a ; N(R 6 )C(O)N(R 6a R 6b ); N(R 6 )C(CO)OR 6a ; OC(O)N(R 6 R 6a ); or T;
R 1a , R 1b are independently selected from the group consisting of H; allyl; benzyl; CH 2 —C(O)NH 2 ; CH 2 —COOH; CH 2 —C(O)O—C 1-6 alkyl; C 1-6 alkyl; and C 3-7 cycloalkyl, wherein C 1-6 alkyl and C 3-7 cycloalkyl are optionally substituted with one or more R 1c , wherein R 1c is independently halogen; C 1-6 alkyl; —CH═CH 2 ; phenyl; C(O)NH 2 ; COOH; C(O)O—C 1-6 alkyl or C 3-7 cycloalkyl;
Optionally A and R 1a form together with the nitrogen to which they are attached to a heterocycle or heterobicycle optionally substituted with one or more R 7 , which are the same or different;
R 6 , R 6a R 6b are independently selected from the group consisting of H; C 1-6 alkyl; and T, wherein C 1-6 alkyl is optionally substituted with one or more halogen, which are the same of different;
T is C 3-7 cycloalkyl; heterocyclyl; heterobicyclyl; phenyl; naphthyl; indenyl; indanyl; tetralinyl; decalinyl; or adamantyl, wherein T is optionally substituted with one or more R 7 , which are the same or different;
R 7 is independently halogen; CN; COOR 8 ; OR 8 ; C(O)N(R 8 R 8a ); S(O) 2 N(R 8 R 8a ); S(O)N(R 8 R 8a ); S(O) 2 R 8 ; N(R 8 )S(O) 2 N(R 8a R 8b ); SR 8 ; N(R 8 R 8a ); OC(O)R 8 ; N(R 8 )C(O)R 8a ; N(R 8 )S(O) 2 R 8a ; N(R 8 )S(O)R 8a ; N(R 8 )C(O)N(R 8a R 8b ); N(R 8 )C(O)OR 8a ; OC(O)N(R 8 R 8a ); oxo (═O), where the ring is at least partially saturated; C(O)R 8 ; T 1 ; or C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted with one or more R 9 ;
R 8 , R 8a , R 8b are independently selected from the group consisting of H; T 1 ; and C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted with one or more R 10 ;
R 9 , R 10 are independently selected from the group consisting of halogen; CN; COOR 11 ; OR 11 ; C(O)R 11 ; C(O)N(R 11 R 11a ); S(O) 2 N(R 11 R 11a ); S(O)N(R 11 R 11a ); S(O) 2 R 11 ; N(R 11 )S(O) 2 N(R 11a R 11b ); SR 11 ; N(R 11 R 11a ); OC(O)R 11 ; N(R 11 )C(O)R 11a ; N(R 11 )SO 2 R 11a ; N(R 11 )S(O)R 11a ; N(R 11 )C(O)N(R 11a R 11b ); N(R 11 )C(O)OR 11a ; OC(O)N(R 11 R 11a ); and T 1 ;
R 11 , R 11a , R 11b are independently selected from the group consisting of H; C 1-6 alkyl; and T 1 ;
T 1 is C 3-7 cycloalkyl; heterocyclyl; heterobicyclyl; phenyl; naphthyl; indenyl; indanyl; tetralinyl; decalinyl; or adamantyl, wherein T 1 is optionally substituted with one or more R 12 , wherein R 12 is independently halogen; CN; COOR 13 ; OR 13 ; C(O)N(R 13 R 13a ); S(O) 2 N(R 13 R 13a ); S(O)N(R 13 R 13a ); S(O) 2 R 13 ; N(R 13 )S(O) 2 N(R 13a R 13b ); SR 13 ; N(R 13 R 13a ); OC(O)R 13 ; N(R 13 )C(O)R 13a ; N(R 13 )S(O) 2 R 13a ; N(R 13 )S(O)R 13a ; N(R 13 )C(O)N(R 13a R 13b ); N(R 13 )C(O)OR 13a ; OC(O)N(R 13 R 13a ); oxo (═O), where the ring is at least partially saturated; C(O)R 13 ; C 1-6 alkyl; phenyl; C 3-7 cycloalkyl; or heterocyclyl, wherein C 1-6 alkyl; phenyl; C 3-7 cycloalkyl; and heterocyclyl are optionally substituted with one or more halogen, which are the same or different;
R 13 , R 13a , R 13b are independently selected from the group consisting of H; C 1-6 alkyl; phenyl; C 3-7 cycloalkyl; and heterocyclyl, wherein C 1-6 alkyl; phenyl; C 3-7 cycloalkyl; and heterocyclyl are optionally substituted with one or more halogen, which are the same or different;
Z 1 is ═O or ═S;
Optionally Z 1 is ═N—R 15 and R 15 , R 3 jointly form together with the atoms to which they are attached a heterocycle or heterobicycle, wherein the heterocycle or heterobicycle is optionally substituted with one or more R 16 ;
Z 2 is O; S; or N—R 14 ;
R 3 , R 14 are independently selected from the group consisting of H; T 2 ; C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted with one or more R 17 , provided that when one of R 3 and R 14 is H and the other is ethyl, R 17 is other than —COOH;
Optionally R 3 , R 14 jointly form together with the nitrogen to which they are attached a heterocycle or heterobicycle, wherein the heterocycle or heterobicycle is optionally substituted with one or more R 18 ;
T is C 3-7 cycloalkyl, heterocyclyl; heterobicyclyl; phenyl; naphthyl; indenyl; indanyl; tetralinyl; decalinyl; or adamantyl, wherein T 2 is optionally substituted with one or more R 19 ; provided that when A is phenyl; Y is —S(O) 2 NH—, wherein the sulfur is attached to A; R 1 , R 2 are H; X 1 , X 3 , X 4 are CH; X 2 is C—R 4 , wherein R 4 is OCH 3 ; Z 1 is ═O; and Z 2 is NH, T 2 is other than unsubstituted phenyl;
R 16 , R 18 , R 19 are independently selected from the group consisting of halogen; CN; COOR 20 ; OR 20 ; C(O)N(R 20 R 20a ); S(O) 2 N(R 20 R 20a ); S(O)N(R 20 R 20a ); S(O) 2 R 20 ; N(R 20 )S(O) 2 N(R 20a R 20b ); SR 20 ; N(R 20 R 20a ); OC(O)R 20 ; N(R 20 )C(O)R 20a ; N(R 20 )S(O) 2 R 20a ; N(R 20 )S(O)R 20a ; N(R 20 )C(O)N(R 20a R 20b ); N(R 20 )C(O)OR 20a ; OC(O)N(R 20 R 20a ); oxo (═O), where the ring is at least partially saturated; C(O)R 20 ; C 1-6 alkyl; phenyl; heterocyclyl; and C 3-7 cycloalkyl, wherein C 1-6 alkyl; phenyl; heterocyclyl; and C 3-7 cycloalkyl are optionally substituted with one or more R 21 ;
R 20 , R 20a , R 20b are independently selected from the group consisting of H; phenyl; heterocyclyl; C 3-7 cycloalkyl and C 1-6 alkyl, wherein phenyl; heterocyclyl; C 3-7 cycloalkyl; and C 1-6 alkyl are optionally substituted with one or more halogen, which are the same or different;
R 17 , R 21 are independently selected from the group consisting of halogen; CN; COOR 22 ; OR 22 ; C(O)R 22 ; C(O)N(R 22 R 22a ); S(O) 2 N(R 22 R 22a ); S(O)N(R 22 R 22a ); S(O) 2 R 22 ; N(R 22 )S(O) 2 N(R 22a R 22b ); SR 22 ; N(R 22 R 22a ); OC(O)R 22 ; N(R 22 )C(O)R 22a ; N(R 22 )SO 2 R 22a ; N(R 22 )S(O)R 22a ; N(R 22 )C(O)N(R 22a R 22b ); N(R 22 )C(O)OR 22a ; OC(O)N(R 22 R 22a ); C 1-6 alkyl; phenyl; heterocyclyl; and C 3-7 cycloalkyl, wherein C 1-6 alkyl; phenyl; heterocyclyl; and C 3-7 cycloalkyl are optionally substituted with one or more R 23 ;
R 22 , R 22a , R 22b are independently selected from the group consisting of H; phenyl; heterocyclyl; C 3-7 cycloalkyl and C 1-6 alkyl, wherein phenyl; heterocyclyl; C 3-7 cycloalkyl; and C 1-6 alkyl are optionally substituted with one or more R 23a ;
R 23 , R 23a are independently selected from the group consisting of halogen; CN; COOR 24 ; OR 24 ; C(O)R 24 ; C(O)N(R 24 R 24a ); S(O) 2 N(R 24 R 24a ); S(O)N(R 24 R 24a ); S(O) 2 R 24 ; N(R 24 )S(O) 2 N(R 24a R 24b ); SR 24 ; N(R 24 R 24a ); OC(O)R 24 ; N(R 24 )C(O)R 24a ; N(R 24 )SO 2 R 24a ; N(R 24 )S(O)R 24a ; N(R 24 )C(O)N(R 24a R 24b ); N(R 24 )C(O)OR 24a ; OC(O)N(R 24 R 24a ); and C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted with one or more halogen, which are the same or different;
R 24 , R 24a , R 24b are independently selected from the group consisting of H; C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted with one or more halogen, which are the same or different, together with a pharmaceutically acceptable carrier, further comprising one or more additional compounds or pharmaceutically acceptable salts thereof selected from the group consisting of compounds as defined in claim 25 and not being the first compound; other 11β-HSD1 inhibitors; DPP-IV inhibitors; insulin sensitizers, e.g. PPAR agonists and biguanides; insulin and insulin mimetics; sulfonylureas and other insulin secretagogues; α-glucosidase inhibitors; glucagon receptor antagonists; GLP-1, GLP-1 mimetics, and GLP-1 receptor agonists; GIP, GIP mimetics, and GIP receptor agonists; PACAP, PACAP mimetics, and PACAP receptor 3 agonists; cholesterol lowering agents, e.g. HMG-CoA reductase inhibitors, sequestrants, nicotinyl alcohol, nicotinic acid or a salt thereof, PPARγ agonists, PPARα/γ dual agonists, inhibitors of cholesterol absorption, acyl CoA: cholesterol acyltransferase inhibitors, and anti-oxidants; PPAR agonists; antiobesity compounds; ileal bile acid transporter inhibitors; anti-inflammatory agents; and protein tyrosine phosphatase-1B (PTP-1B) inhibitors; anti-hypertensive compounds; and compounds for the treatment of cardiovascular diseases, particularly atherosclerosis.
53 . A method for treating, controlling, delaying or preventing in a mammalian patient in need of treatment one or more conditions selected from the group consisting of the onset of non-insulin dependent diabetes mellitus, hyperglycemia, low glucose tolerance, insulin resistance, obesity, lipid disorders, dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL levels, high LDL levels, atherosclerosis and its sequelae, vascular restenosis, pancreatitis, abdominal obesity, neurodegenerative disease, retinopathy, nephropathy, neuropathy, Syndrome X, Alzheimer's disease, osteoporosis, cancer, epilepsy, depression, HAART-associated lipodystrophy and other conditions and disorders where insulin resistance is a component or that may be treated by inhibition of the 11β-HSD1 enzyme, wherein the method comprises the administration to said patient of a therapeutically effective amount of a compound of formula (I)
or a pharmaceutically acceptable salt, prodrug or metabolite thereof, wherein
X 1 , X 2 , X 3 , X 4 are independently selected from the group consisting of N; and CR 4 , wherein R 4 is independently H; halogen; CN; C(O)OR 4a ; C(O)N(R 4a R 4b ); OR 4a ; N(R 4a R 4b ); phenyl; C 1-6 alkyl; or C 3-7 cycloalkyl, wherein C 1-6 alkyl and C 3-7 cycloalkyl are optionally substituted with one or more halogen, which are the same or different;
R 4a , R 4b are independently selected from the group consisting of H; C 1-6 alkyl; and C 3-7 cycloalkyl;
R 1 , R 2 are independently selected from the group consisting of H; C 1-6 alkyl; C 3-7 cycloalkyl; and halogen, wherein C 1-6 alkyl and C 3-7 cycloalkyl are optionally substituted with halogen;
Optionally R 1 , R 2 are combined to form oxo (═O);
Y is —N(R 1a )S(O) 2 —; —S(O) 2 N(R 1b )—; or —N(R 1a )S(O) 2 N(R 1b )—;
A is T; or C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted with one or more R 5 , wherein R 5 is independently halogen; CN; COOR 6 ; OR 6 ; C(O)N(R 6 R 6a ); S(O) 2 N(R 6 R 6a ); S(O)N(R 6 R 6a ); S(O) 2 R 6 ; N(R 6 )S(O) 2 N(R 6a R 6b ); SR 6 ; N(R 6 R 6a ); OC(O)R 6 ; N(R 6 )C(O)R 6a ; N(R 6 )S(O) 2 R 6a ; N(R 6 )S(O)R 6a ; N(R 6 )C(O)N(R 6a R 6b ); N(R 6 )C(CO)OR 6a ; OC(O)N(R 6 R 6a ); or T;
R 1a , R 1b are independently selected from the group consisting of H; allyl; benzyl; CH 2 —C(O)NH 2 ; CH 2 —COOH; CH 2 —C(O)O—C 1-6 alkyl; C 1-6 alkyl; and C 3-7 cycloalkyl, wherein C 1-6 alkyl and C 3-7 cycloalkyl are optionally substituted with one or more R 1c , wherein R 1c is independently halogen; C 1-6 alkyl; —CH═CH 2 ; phenyl; C(O)NH 2 ; COOH; C(O)O—C 1-6 alkyl or C 3-7 cycloalkyl;
Optionally A and R 1a form together with the nitrogen to which they are attached to a heterocycle or heterobicycle optionally substituted with one or more R 7 , which are the same or different;
R 6 , R 6a R 6b are independently selected from the group consisting of H; C 1-6 alkyl; and T, wherein C 1-6 alkyl is optionally substituted with one or more halogen, which are the same of different;
T is C 3-7 cycloalkyl; heterocyclyl; heterobicyclyl; phenyl; naphthyl; indenyl; indanyl; tetralinyl; decalinyl; or adamantyl, wherein T is optionally substituted with one or more R 7 , which are the same or different;
R 7 is independently halogen; CN; COOR 8 ; OR 8 ; C(O)N(R 8 R 8a ); S(O) 2 N(R 8 R 8a ); S(O)N(R 8 R 8a ); S(O) 2 R 8 ; N(R 8 )S(O) 2 N(R 8a R 8b ); SR 8 ; N(R 8 R 8a ); OC(O)R 8 ; N(R 8 )C(O)R 8a ; N(R 8 )S(O) 2 R 8a ; N(R 8 )S(O)R 8a ; N(R 8 )C(O)N(R 8a R 8b ); N(R 8 )C(O)OR 8a ; OC(O)N(R 8 R 8a ); oxo (═O), where the ring is at least partially saturated; C(O)R 8 ; T 1 ; or C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted with one or more R 9 ;
R 8 , R 8a , R 8b are independently selected from the group consisting of H; T 1 ; and C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted with one or more R 10 ;
R 9 , R 10 are independently selected from the group consisting of halogen; CN; COOR 11 ; OR 11 ; C(O)R 11 ; C(O)N(R 11 R 11a ); S(O) 2 N(R 11 R 11a ); S(O)N(R 11 R 11a ); S(O) 2 R 11 ; N(R 11 )S(O) 2 N(R 11a R 11b ); SR 11 ; N(R 11 R 11a ); OC(O)R 11 ; N(R 11 )C(O)R 11a ; N(R 11 )SO 2 R 11a ; N(R 11 )S(O)R 11a ; N(R 11 )C(O)N(R 11a R 11b ); N(R 11 )C(O)OR 11a ; OC(O)N(R 11 R 11a ); and T 1 ;
R 11 , R 11a , R 11b are independently selected from the group consisting of H; C 1-6 alkyl; and T 1 ;
T 1 is C 3-7 cycloalkyl; heterocyclyl; heterobicyclyl; phenyl; naphthyl; indenyl; indanyl; tetralinyl; decalinyl; or adamantyl, wherein T 1 is optionally substituted with one or more R 12 , wherein R 12 is independently halogen; CN; COOR 13 ; OR 13 ; C(O)N(R 13 R 13a ); S(O) 2 N(R 13 R 13a ); S(O)N(R 13 R 13a ); S(O) 2 R 13 ; N(R 13 )S(O) 2 N(R 13a R 13b ); SR 13 ; N(R 13 R 13a ); OC(O)R 13 ; N(R 13 )C(O)R 13a ; N(R 13 )S(O) 2 R 13a ; N(R 13 )S(O)R 13a ; N(R 13 )C(O)N(R 13a R 13b ); N(R 13 )C(O)OR 13a ; OC(O)N(R 13 R 13a ); oxo (═O), where the ring is at least partially saturated; C(O)R 13 ; C 1-6 alkyl; phenyl; C 3-7 cycloalkyl; or heterocyclyl, wherein C 1-6 alkyl; phenyl; C 3-7 cycloalkyl; and heterocyclyl are optionally substituted with one or more halogen, which are the same or different;
R 13 , R 13a , R 13b are independently selected from the group consisting of H; C 1-6 alkyl; phenyl; C 3-7 cycloalkyl; and heterocyclyl, wherein C 1-6 alkyl; phenyl; C 3-7 cycloalkyl; and heterocyclyl are optionally substituted with one or more halogen, which are the same or different;
Z 1 is ═O or ═S;
Optionally Z 1 is ═N—R 15 and R 15 , R 3 jointly form together with the atoms to which they are attached a heterocycle or heterobicycle, wherein the heterocycle or heterobicycle is optionally substituted with one or more R 16 ;
Z 2 is O; S; or N—R 14 ;
R 3 , R 14 are independently selected from the group consisting of H; T 2 ; C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted with one or more R 17 , provided that when one of R 3 and R 14 is H and the other is ethyl, R 17 is other than —COOH;
Optionally R 3 , R 14 jointly form together with the nitrogen to which they are attached a heterocycle or heterobicycle, wherein the heterocycle or heterobicycle is optionally substituted with one or more R 18 ;
T 2 is C 3-7 cycloalkyl, heterocyclyl; heterobicyclyl; phenyl; naphthyl; indenyl; indanyl; tetralinyl; decalinyl; or adamantyl, wherein T 2 is optionally substituted with one or more R 19 ; provided that when A is phenyl; Y is —S(O) 2 NH—, wherein the sulfur is attached to A; R 1 , R 2 are H; X 1 , X 3 , X 4 are CH; X 2 is C—R 4 , wherein R 4 is OCH 3 ; Z 1 is ═O; and Z 2 is NH, T 2 is other than unsubstituted phenyl;
R 16 , R 18 , R 19 are independently selected from the group consisting of halogen; CN; COOR 20 ; OR 20 ; C(O)N(R 20 R 20a ); S(O) 2 N(R 20 R 20a ); S(O)N(R 20 R 20a ); S(O) 2 R 20 ; N(R 20 )S(O) 2 N(R 20a R 20b ); SR 20 ; N(R 20 R 20a ); OC(O)R 20 ; N(R 20 )C(O)R 20a ; N(R 20 )S(O) 2 R 20a ; N(R 20 )S(O)R 20a ; N(R 20 )C(O)N(R 20a R 20b ); N(R 20 )C(O)OR 20a ; OC(O)N(R 20 R 20a ); oxo (═O), where the ring is at least partially saturated; C(O)R 20 ; C 1-6 alkyl; phenyl; heterocyclyl; and C 3-7 cycloalkyl, wherein C 1-6 alkyl; phenyl; heterocyclyl; and C 3-7 cycloalkyl are optionally substituted with one or more R 21 ;
R 20 , R 20a , R 20b are independently selected from the group consisting of H; phenyl; heterocyclyl; C 3-7 cycloalkyl and C 1-6 alkyl, wherein phenyl; heterocyclyl; C 3-7 cycloalkyl; and C 1-6 alkyl are optionally substituted with one or more halogen, which are the same or different;
R 17 , R 21 are independently selected from the group consisting of halogen; CN; COOR 22 ; OR 22 ; C(O)R 22 ; C(O)N(R 22 R 22a ); S(O) 2 N(R 22 R 22a ); S(O)N(R 22 R 22a ); S(O) 2 R 22 ; N(R 22 )S(O) 2 N(R 22a R 22b ); SR 22 ; N(R 22 R 22a ); OC(O)R 22 ; N(R 22 )C(O)R 22a ; N(R 22 )SO 2 R 22a ; N(R 22 )S(O)R 22a ; N(R 22 )C(O)N(R 22a R 22b ); N(R 22 )C(O)OR 22a ; OC(O)N(R 22 R 22a ); C 1-6 alkyl; phenyl; heterocyclyl; and C 3-7 cycloalkyl, wherein C 1-6 alkyl; phenyl; heterocyclyl; and C 3-7 cycloalkyl are optionally substituted with one or more R 23 ;
R 22 , R 22a , R 22b are independently selected from the group consisting of H; phenyl; heterocyclyl; C 3-7 cycloalkyl and C 1-6 alkyl, wherein phenyl; heterocyclyl; C 3-7 cycloalkyl; and C 1-6 alkyl are optionally substituted with one or more R 23a ;
R 23 , R 23a are independently selected from the group consisting of halogen; CN; COOR 24 ; OR 24 ; C(O)R 24 ; C(O)N(R 24 R 24a ); S(O) 2 N(R 24 R 24a ); S(O)N(R 24 R 24a ); S(O) 2 R 24 ; N(R 24 )S(O) 2 N(R 24a R 24b ); SR 24 ; N(R 24 R 24a ); OC(O)R 24 ; N(R 24 )C(O)R 24a ; N(R 24 )SO 2 R 24a ; N(R 24 )S(O)R 24a ; N(R 24 )C(O)N(R 24a R 24b ); N(R 24 )C(O)OR 24a ; OC(O)N(R 24 R 24a ); and C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted with one or more halogen, which are the same or different;
R 24 , R 24a , R 24b are independently selected from the group consisting of H; C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted with one or more halogen, which are the same or different.
54 . A process for the preparation of a compound as defined in claim 52 , comprising the steps of
Reducing a compound of formula (II)
and
Coupling the resulting amine (III)
with A-Y—Cl, wherein A is T or C 1-6 alkyl; or
with A-H and SO 2 Cl 2 , wherein A is T-N(R 1c )—.Cited by (0)
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